In the undeveloped world, over 350 million people are at risk from neglected tropical diseases such as malaria, African sleeping sickness, Chagas disease and Leishmaniasis. Existing therapies to treat such neglected tropical diseases are increasingly ineffective due to the development of resistance by the parasites that underpin these conditions to drugs used both in disease prevention and treatment.
Worldwide, an estimated 200 to 300 million malarial infections occur each year. Approximately 1 million people die each year from malaria and the disease is one of the world's biggest killers. Malaria is caused by an infection of the red blood cells with a tiny organism or parasite called protozoa. Five species of the protozoa Plasmodium are known to cause infection in humans: Plasmodium falciparum (Pf); Plasmodium vivax (Pv); Plasmodium ovale; Plasmodium malariae; and Plasmodium knowlesi. The injection of protozoa of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae into the blood stream, is effected by a single source, the bite of the female Anopheles mosquito. Thus there is a need for agents which are effective against Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi infections.
The most life-threatening form of malaria is attributable to blood cells infected with the Plasmodium falciparum parasite, and can cause kidney or liver failure, coma and death. About 2% of people infected with falciparum malaria die and with an estimated one child dying every 45 seconds from falciparum malarial infections the need for an effective treatment could not be higher. Thus there is a need for agents which are: effective against Plasmodium falciparum infections; effective against Plasmodium falciparum and Plasmodium vivax infections; effective against Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi infections.
Plasmodium species require two hosts, human and mosquito for completion of its life-cycle. In humans the infection is initiated by the inoculation of sporozoites in the saliva of an infected mosquito. Once inside the body the sporozoites migrate to the liver and there infect hepatocytes where they differentiate, via the exoerythrocytic intracellular stage, into the merozoite stage which infects red blood cells to initiate cyclical replication in the asexual blood stage. The life-cycle is completed by the differentiation of a number of merozoites in the red blood cells into sexual stage gametocytes which are ingested by the mosquito, where they develop through a series of stages in the mid gut to produce sporozoites which migrate to the salivary gland.
Many countries have been experiencing resurgence in malaria cases caused by Plasmodium falciparum due to the spread of parasites which are increasingly resistant to both chloroquine, the drug most widely used for prevention and treatment as well as newer, alternative treatments such as artesunate. See, Wellems et al, JID 2001; 184 (15 September) and Noedl et al, N Engl J Med 2008; 359:2619-2620 (11 December). The development of new anti-malarial treatments is of great importance particularly given the rapid spread of parasite resistance even within newer artemisinin-based therapies.
In the battle against the continued spread of both malarial infection and the parasite resistance to malaria compounds having the potential to both combat the infection and also impact upon the parasite growth cycle, particularly against gametocyte development and thereby impacting upon subsequent transmission potential, would be highly desirable.
A further strand in assisting effective treatment of malarial infections is the need for therapies which can be dosed efficiently in difficult conditions. As such, single-dose, oral, rectal or parenteral therapies, particularly sustained or modified release therapies would be of value.
Thus there is a need for new and effective anti-malarial agents. In particular there is a need for new anti-malarial agents which: are effective against drug-resistant parasites; are effective against drug-resistant Plasmodium falciparum infections such as for example Chloroquine-resistant Plasmodium falciparum infections; which are active against gametocytes; have transmission-blocking potential; which are active against liver stage; which can be used for single-dose treatment; and/or which can be used for prophylactic treatment.
The present invention provides a novel class of class of quinolone-4-carboxamide compounds Plasmodium falciparum 3D7 inhibitors having potential as anti-malarial agents. The novel class of quinolone-4-carboxamide compounds according to the present invention have potential for the treatment of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi infections. In particular the novel class of class of quinolone-4-carboxamide compounds according to the present invention have potential for the treatment of Plasmodium falciparum infections; Plasmodium falciparum and Plasmodium vivax infections; Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi infections.
Desirable properties of compounds of formula (I) according to the present invention include: potency against Plasmodium falciparum 3D7; low toxicity in MRC-5 or HepG2 cells; both desirable Plasmodium falciparum (Pf) 3D7 potency and low toxicity in MRC-5 or HepG2; desirable Plasmodium falciparum and Plasmodium vivax (Pv) activity against clinical isolates; desirable transmission blocking activity; gametocyte inhibitory potential; activity against dormant liver stage forms; good biopharmaceutical properties such as physical stability; good solubility profiles; appropriate metabolic stability; desirable ADME properties (adsorption, distribution, metabolism, excretion).